Amantadine and related compounds have been shown to moderate dopamine levels in the brain and also to have certain activity as antivirals. Additionally, these compounds have activity in the treatment of Parkinson's disease. Generally, amantadine and amantadine analogs have fallen out of favor as therapeutics owing to many strains of influenza virus being refractory towards these compounds, while as an anti-Parkinsonian drug side effects outweighed clinical efficacy. Nonetheless, amantadine and a amantadine analogs are antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.
Amantadine and amantadine analogs create CNS side effects of nervousness, anxiety, agitation, insomnia, and accentuate pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. The need to screen patients for a history of seizures and psychiatric symptoms in an effort to preclude such side effects has also limited use of amantadine and amantadine analogs. The aliphatic and rigid structure of the adamantane core of these therapeutics with a single polar amine functionality makes these compounds prone to segregation in a phospholipid bilayer with the amine moiety oriented with the polar phosphate groups of the bilayer and the adamantane core within the lipid portion of the bilayer. As a result, the ability of ability of amantadine and amantadine analogs to transit the blood brain barrier and provide therapeutic effect is limited, while the propensity to cause side effects through cellular membrane disruption is high.
Thus, there exists a need for an improved composition for systemic and/or intrathecal delivery of amantadine and its analogs that mitigate side effects.